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Leukaemic cells, but not their myeloid counterparts, largely depend on glutamine. Glutamate dehydrogenase 1 (GDH1) is a regulation enzyme in glutaminolysis. However, its role in AML remains unknown. Here, we reported that GDH1 was highly expressed in AML: high GDH1 was one of the independent negative prognostic factors in AML cohort. The dependence of leukaemic cells on GDH1 was proved both in vitro and in vivo. High GDH1 promoted cell proliferation and reduced survival time of leukaemic mice. Targeting GDH1 eliminated the blast cells and delayed AML progression. Mechanistically, GDH1 knockdown inhibited glutamine uptake by downregulating SLC1A5. Moreover, GDH1 invalidation also inhibited SLC3A2 and abrogated the cystine\u2010glutamate antiporter system Xc<jats:sup>\u2212<\/jats:sup>. The reduced cystine and glutamine disrupted the synthesis of glutathione (GSH) and led to the dysfunction of glutathione peroxidase\u20104 (GPX4), which maintains the lipid peroxidation homeostasis by using GSH as a co\u2010factor. Collectively, triggering ferroptosis in AML cells in a GSH depletion manner, GDH1 inhibition was synthetically lethal with the chemotherapy drug cytarabine. Ferroptosis induced by inhibiting GDH1 provides an actionable therapeutic opportunity and a unique target for synthetic lethality to facilitate the elimination of malignant AML cells.<\/jats:p>","DOI":"10.1111\/bjh.18884","type":"journal-article","created":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T07:00:13Z","timestamp":1685084413000},"page":"566-577","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Glutamate dehydrogenase 1: A novel metabolic target in inhibiting acute myeloid leukaemia progression"],"prefix":"10.1111","volume":"202","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2996-6867","authenticated-orcid":false,"given":"Zhixin","family":"Ma","sequence":"first","affiliation":[{"name":"Key Laboratory of Reproductive Genetics, and Women's Hospital, School of Medicine Zhejiang University  Hangzhou China"},{"name":"Clinical Prenatal Diagnosis Center, Women's Hospital, School of Medicine Zhejiang 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